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Purpose of Review: De novo lipogenesis (DNL) is a metabolic process occurring mainly within the liver, in humans. Insulin is a primary signal for promoting DNL; thus, nutritional state is a key determinant for upregulation of the pathway. However, the effects of dietary macronutrient composition on hepatic DNL remain unclear. Nor is it clear if a nutrition-induced increase in DNL results in accumulation of intra-hepatic triglyceride (IHTG); a mechanism often proposed for pathological IHTG. Here, we review the latest evidence surrounding the nutritional regulation of hepatic DNL., Recent Findings: The role of carbohydrate intake on hepatic DNL regulation has been well studied, with only limited data on the effects of fats and proteins. Overall, increasing carbohydrate intake typically results in an upregulation of DNL, with fructose being more lipogenic than glucose. For fat, it appears that an increased intake of n-3 polyunsaturated fatty acids downregulates DNL, whilst, in contrast, an increased dietary protein intake may upregulate DNL., Summary: Although DNL is upregulated with high-carbohydrate or mixed-macronutrient meal consumption, the effects of fat and protein remain unclear. Additionally, the effects of different phenotypes (including sex, age, ethnicity, and menopause status) in combination with different diets (enriched in different macronutrients) on hepatic DNL requires elucidation., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Intrahepatic triglyceride (IHTG) content is determined by substrate flux to, fatty acid synthesis and partitioning within, and triglyceride disposal from the liver. Dysregulation of these processes may cause IHTG accumulation, potentially leading to nonalcoholic fatty liver disease. The aetiology of IHTG accumulation has not been fully elucidated; however, environmental factors and heritability are important. Here, we review recent evidence regarding the contribution of metabolic and genetic components of IHTG accumulation., Recent Findings: Obesity and insulin resistance are the primary metabolic drivers for IHTG accumulation. These risk factors have pronounced and seemingly overlapping effects on all processes involved in determining IHTG content. The strong and interchangeable associations between obesity, insulin resistance and IHTG make it challenging to determine their relative contributions. Genome-wide association studies have identified a growing list of single nucleotide polymorphisms associated with IHTG content and recent work has begun to elucidate their mechanistic effects. The mechanisms underlying metabolic and genetic drivers of IHTG appear to be distinct., Summary: Both metabolic and genetic factors influence IHTG content by apparently distinct mechanisms. Further work is needed to determine metabolic and genetic interaction effects, which may lead to more personalized and potentially efficacious therapeutic interventions. The development of a comprehensive polygenic risk score for IHTG content may help facilitate this., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: We recently showed that measurement of the susceptibility of LDL (low-density lipoprotein) to aggregation is an independent predictor of cardiovascular events. We now wished to compare effects of overfeeding different dietary macronutrients on LDL aggregation, proteoglycan-binding of plasma lipoproteins, and on the concentration of oxidized LDL in plasma, 3 in vitro parameters consistent with increased atherogenicity., Approach and Results: The participants (36 subjects; age, 48+/-10 years; body mass index, 30.9+/-6.2 kg/m2) were randomized to consume an extra 1000 kcal/day of either unsaturated fat, saturated fat, or simple sugars (CARB) for 3 weeks. We measured plasma proatherogenic properties (susceptibility of LDL to aggregation, proteoglycan-binding, oxidized LDL) and concentrations and composition of plasma lipoproteins using nuclear magnetic resonance spectroscopy, and in LDL using liquid chromatography mass spectrometry, before and after the overfeeding diets. LDL aggregation increased in the saturated fat but not the other groups. This change was associated with increased sphingolipid and saturated triacylglycerols in LDL and in plasma and reduction of clusterin on LDL particles. Proteoglycan binding of plasma lipoproteins decreased in the unsaturated fat group relative to the baseline diet. Lipoprotein properties remained unchanged in the CARB group., Conclusions: The type of fat during 3 weeks of overfeeding is an important determinant of the characteristics and functional properties of plasma lipoproteins in humans.

Introduction: Exogenous ketones potentially provide an alternative, energetically advantageous fuel to power exercising skeletal muscle. However, there is limited evidence regarding their relative contribution to energy expenditure during exercise. Furthermore, the effect of blood ketone concentration and exercise intensity on exogenous ketone oxidation rates is unknown., Methods: Six athletes completed cycling ergometer exercise on three occasions within a single-blind, random-order controlled, crossover design study. Exercise duration was 60 min, consisting of 20-min intervals at 25%, 50%, and 75% maximal power output (WMax). Participants consumed (i) bitter flavored water (control), (ii) a low-dose β-hydroxybutyrate (βHB) ketone monoester (KME; 252 mg·kg BW-1, "low ketosis"), or (iii) a high-dose βHB KME (752 mg·kg BW-1, "high ketosis"). The KME contained a 13C isotope label, allowing for the determination of whole-body exogenous βHB oxidation rates through sampled respiratory gases., Results: Despite an approximate doubling of blood βHB concentrations between low- and high-ketosis conditions (~2 mM vs ~4.4 mM), exogenous βHB oxidation rates were similar at rest and throughout exercise. The contribution of exogenous βHB oxidation to energy expenditure peaked during the 25% WMax exercise intensity but was relatively low (4.46% ± 2.71%). Delta efficiency during cycling exercise was significantly greater in the low-ketosis (25.9% ± 2.1%) versus control condition (24.1% ± 1.9%; P = 0.027)., Conclusions: Regardless of exercise intensity, exogenous βHB oxidation contributes minimally to energy expenditure and is not increased by elevating circulating concentrations greater than ~2 mM. Despite low exogenous βHB oxidation rates, exercise efficiency was significantly improved when blood βHB concentration was raised to ~2 mM., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)

Purpose of Review: Prevalence of metabolic-associated fatty liver disease (MAFLD) is increasing, and as pharmacological treatment does not exist, lifestyle interventions (i.e. diet and exercise) represent the cornerstone management and treatment strategy. Although the available data clearly demonstrate that changes in lifestyle influence intrahepatic triglyceride (IHTG) content, the mechanisms through which this is achieved are seldom investigated. Here, we review recent evidence demonstrating the influence of lifestyle interventions on hepatic fatty acid metabolism and IHTG content., Recent Findings: Diet and exercise influence IHTG content through various, and often interrelated factors. These include alterations in whole-body and tissue-specific insulin sensitivity, which may influence the flux of fatty acid and lipogenic substrates to the liver, and changes in intrahepatic fatty acid synthesis and partitioning. Notably, there are only a few studies that have investigated intrahepatic fatty acid metabolism in vivo in humans before and after an intervention., Summary: Lifestyle interventions represent an effective means of influencing hepatic fatty acid metabolism. IHTG content is decreased without weight-loss either through exercise or by changing the macronutrient composition of the diet, although what the optimal macronutrient composition is to achieve this has yet to be defined.

Purpose of Review: Upper body abdominal and lower body gluteofemoral fat depot masses display opposing associations with plasma lipid and lipoprotein and cardiovascular disease (CVD) risk profiles. We review developments on adipose tissue fatty acid metabolism in the context of body fat distribution and how that might be related to adverse lipid and lipoprotein profiles and CVD risk., Recent Findings: Recent data have confirmed the paradoxical relationship of upper abdominal and lower body gluteofemoral adiposity and CVD risk. Mechanistically, this is likely to reflect the different ways fat depots handle lipid storage and release, which impacts directly and indirectly on lipid and lipoprotein metabolism. The upper body enhances immediate fat storage pathway with rapid uptake of dietary-derived fatty acids, whereas the lower body fat depot has a reduced lipid turnover accommodating a slower fat redistribution. Body fat distribution and the fat depots' ability to undergo appropriate expansion when fat storage is required, rather than overall body fatness, appear as the important determinant of metabolic health., Summary: A focus on fat distribution in overweight people, preferably using precise imaging methods, rather than quantifying total body fatness, is likely to provide the medical community with better tools to stratify and treat patients with obesity-related complications.

Purpose of Review: A net retention of triacylglycerol within the liver is a prerequisite for the development of nonalcoholic fatty liver disease. The accumulation of liver fat reflects an imbalance between fatty acid input and disposal. Here we summarize recent research into understanding the fate of fatty acids within the hepatocyte., Recent Findings: Several recent studies have elucidated the contribution of different sources of fatty acids to liver fat and to plasma triacylglycerol. Some recent studies have suggested that, contrary to expectations, hepatic fatty acid oxidation is upregulated in insulin-resistant individuals. A recent observation shows the potential importance of fatty acid transformation, especially desaturation, to determination of metabolic fate. These studies highlight our lack of understanding of the regulation of metabolic partitioning of fatty acids within the human liver., Summary: The regulation of hepatic fatty acid partitioning involves many factors; not least insulin. Insulin undoubtedly regulates the supply of fatty acids to the liver from adipose tissue; however, whether insulin has a direct intrahepatic effect on hepatic fatty acid partitioning, in humans, remains unclear. The transformation of fatty acids, by desaturases, may have an important role in aiding the disposal of saturated fatty acids via oxidative pathways. Factors that upregulate hepatic fatty acid oxidation need to be elucidated.